The present invention relates to medicaments comprising, as active principle, at least one compound of formula: 
or one of their stereoisomers or their salts with an inorganic or organic acid, to novel compounds of formula (I) and to their preparation.
In the formula (I), either R1 represents a xe2x80x94CH(Ra)xe2x80x94CHOHxe2x80x94CHOHxe2x80x94CH2OH chain and
R2 represents a xe2x80x94CH2xe2x80x94CHOHxe2x80x94CHOHxe2x80x94CH2OH chain,
or R1 represents a xe2x80x94CHOHxe2x80x94CHFxe2x80x94CHOHxe2x80x94CH2OH chain and R2 represents a xe2x80x94CH2xe2x80x94CHFxe2x80x94CHOHxe2x80x94CH2OH chain,
or R1 represents a xe2x80x94CHOHxe2x80x94CHOHxe2x80x94CHOHxe2x80x94Rb chain and R2 represents a xe2x80x94CH2xe2x80x94CHOHxe2x80x94CHOHxe2x80x94Rb chain,
or R1 represents a xe2x80x94CH2xe2x80x94CHOHxe2x80x94CHOHxe2x80x94CH2OH chain and R2 represents a xe2x80x94CH2xe2x80x94CHOHxe2x80x94CHOHxe2x80x94CH2OH chain,
or R1 and R2 are identical and each represent a xe2x80x94(CHOH)nxe2x80x94CH2OH chain in which n is equal to 1, 2, 3 or 4,
Ra represents an alkoxy radical (1-6 C in a straight or branched chain) or a fluorine atom,
Rb represents a carboxyl, xe2x80x94COxe2x80x94NH2 or xe2x80x94CH2xe2x80x94NH2 radical.
As the compounds of formula (I) comprise several asymmetric carbons, [lacuna] exhibit stereoisomeric forms. These various stereoisomers form part of the invention.
The compound of formula: 
is described in Nippon Shokuhin Kogyo Gakkaishi, 37 (2), 154 (1990), Agric. Biol. Chem., 44 (5), 1189 (1980), Carbohydr. Res., 67 (2), 549 (1978).
The compound of formula: 
is described in Dev. Food Sci., 13, 85 (1986).
No pharmacological activity is described for these derivatives.
The other compounds of formula (I) are novel and, as such, form part of the present invention.
The preferred medicaments are those which comprise, as active principle, at least one of the following compounds:
-4-[6-(2,3,4-Trihydroxybutyl)pyrazin-2-yl]-4-methoxy-butane-1,2,3-triol,
-4-[6-(2,3,4-Trihydroxybutyl)pyrazin-2-yl]-4-fluorobutane-1,2,3-triol,
-1-[6-(2-Fluoro-3,4-dihydroxybutyl)pyrazin-2-yl]-2-fluorobutane-1,3,4-triol,
-1-[6-(2,3-Dihydroxy-4-aminobutyl)pyrazin-2-yl]-4-aminobutane-1,2,3-triol,
-4-[6-(2,3-Dihydroxy-4-carboxypropyl)pyrazin-2-yl]-2,3,4-trihydroxybutanoic acid,
-4-[6-(2,3-Dihydroxy-4-carbamoylpropyl)pyrazin-2-yl]-2,3,4-trihydroxybutanamide,
-4-[6-(2,3,4-Trihydroxybutyl)pyrazin-2-yl]butane-1,2,3-triol,
1-[6-(1,2-Dihydroxyethyl)pyrazin-2-yl]ethane-1,2-diol,
1-[6-(1,2,3-Trihydroxypropyl)pyrazin-2-yl]propane-1,2,3-triol,
1-[6-(1,2,3,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1,2,3,4-tetraol,
1-[6-(1,2,3,4,5-Pentahydroxypentyl)pyrazin-2-yl]-pentane-1,2,3,4S,5-pentaol,
their stereoisomers and their salts with a pharmaceutically acceptable inorganic or organic acid.
The particularly preferred medicaments are those which comprise a compound chosen from the following compounds:
-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4R-methoxybutane-1,2R,3S-triol,
-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-methoxybutane-1,2R,3R-triol,
-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-methoxybutane-1,2R,3S-triol,
-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4R-fluorobutane-1,2R,3R-triol,
-1-[6-(2S-Fluoro-3R,4-dihydroxybutyl)pyrazin-2-yl]-2S-fluorobutane-1R,3R,4-triol,
-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-fluorobutane-1,2R,3R-triol,
-1-[6-(2S,3R-Dihydroxy-4-aminobutyl)pyrazin-2-yl]-4-aminobutane-1R,2R,3R-triol,
-1-[6-(2S,3S-Dihydroxy-4-aminobutyl)pyrazin-2-yl]-4-aminobutane-1R,2R,3S-triol,
-4-[6-(2S,3S-Dihydroxy-4-carboxypropyl)pyrazin-2-yl]-2S,3S,4R-trihydroxybutanoic acid,
-4-[6-(2R,3S-Dihydroxy-4-carboxypropyl)pyrazin-2-yl]-2S,3R,4R-trihydroxybutanoic acid,
-4-[6-(2S,3S-Dihydroxy-4-carbamoylpropyl)pyrazin-2-yl]-2S,3S,4R-trihydroxybutanamide,
-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]butane-1,2R,3S-triol,
-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]butane-1,2R,3R-triol,
1-[6-(1R,2-Dihydroxyethyl)pyrazin-2-yl]ethane-1R,2-diol,
1-[6-(1S,2-Dihydroxyethyl)pyrazin-2-yl]ethane-1S,2-diol,
1-[6-(1R,2S,3-Trihydroxypropyl)pyrazin-2-yl]propane-1R,2S,3-triol,
1-[6-(1S,2R,3-Trihydroxypropyl)pyrazin-2-yl]propane-1S,2R,3-triol,
1-[6-(1S,2S,3-Trihydroxypropyl)pyrazin-2-yl]propane-1S,2S,3-triol,
1-[6-(1R,2R,3R,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol,
1-[6-(1R,2R,3S,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol,
1-[6-(1R,2S,3R,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol,
1-[6-(1R,2S,3S,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol,
1-[6-(1S,2R,3R,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol,
1-[6-(1S,2R,3S,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol,
1-[6-(1S,2S,3R,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol,
1-[6-(1S,2S,3S,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol,
1-[6-(1R,2R,3R,4S,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1R,2R,3R,4S,5-pentaol,
1-[6-(1R,2S,3S,4R,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1R,2S,3S,4R,5-pentaol,
1-[6-(1R,2S,3R,4S,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1R,2S,3R,4S,5-pentaol,
1-[6-(1R,2R,3R,4R,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1R,2R,3R,4R,5-pentaol,
1-[6-(1R,2S,3R,4R,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1R,2S,3R,4R,5-pentaol,
1-[6-(1S,2R,3R,4R,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1S,2R,3R,4R,5-pentaol,
1-[6-(1S,2R,3S,4R,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1S,2R,3S,4R,5-pentaol,
and their salts with a pharmaceutically acceptable inorganic or organic acid.
The even more particularly preferred medicaments are those which comprise a compound chosen from the following compounds:
-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4R-methoxybutane-1,2R,3S-triol,
-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-methoxybutane-1,2R,3R-triol,
-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-methoxybutane-1,2R,3S-triol,
-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4R-fluorobutane-1,2R,3R-triol,
-1-[6-(2s-Fluoro-3R,4-dihydroxybutyl)pyrazin-2-yl]-2S-fluorobutane-1R,3R,4-triol,
-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-fluorobutane-1,2R,3R-triol,
-1-[6-(2S,3R-Dihydroxy-4-aminobutyl)pyrazin-2-yl]-4-aminobutane-1R,2R,3R-triol,
-1-[6-(2S,3S-Dihydroxy-4-aminobutyl)pyrazin-2-yl]-4-aminobutane-1R,2R,3S-triol,
-4-[6-(2S,3S-Dihydroxy-4-carboxypropyl)pyrazin-2-yl]-2S,3S,4R-trihydroxybutanoic acid,
-4-[6-(2R,3S-Dihydroxy-4-carboxypropyl)pyrazin-2-yl]-2S,3R,4R-trihydroxybutanoic acid,
-4-[6-(2S,3S-Dihydroxy-4-carbamoylpropyl)pyrazin-2-yl]-2S,3S,4R-trihydroxybutanamide,
-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]butane-1,2R,3S-triol,
-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]butane-1,2R,3R-triol,
and their salts with an inorganic or organic acid.
The compounds of formula (I) can be prepared by reaction of ammonium formate with one or two derivatives of formula:
OHCxe2x80x94CHOHxe2x80x94Rcxe2x80x83xe2x80x83(II)
in which Rc represents a xe2x80x94CH(Ra)xe2x80x94CHOHxe2x80x94CHOHxe2x80x94CH2OH, xe2x80x94CHOHxe2x80x94CHFxe2x80x94CHOHxe2x80x94CH2OH, xe2x80x94CHOHxe2x80x94CHOHxe2x80x94CHOHxe2x80x94Rb, CH2xe2x80x94CHOHxe2x80x94CHOHxe2x80x94CH2OH or xe2x80x94(CHOH)nxe2x80x94CH2OH chain in which n is equal to 1, 2, 3 or 4, Ra represents an alkoxy radical (1-6 C as a straight or branched chain) or a fluorine atom and Rb represents a carboxyl, xe2x80x94COxe2x80x94NH2 or xe2x80x94CH2xe2x80x94NH2 radical, or one of its stereoisomers.
This reaction is generally carried out in aqueous medium, at a temperature of between 20 C. and 100 C.
The derivatives of formula (II) and their stereoisomers are commercially available or can be obtained from:
a) commercially available aldoses:
by epimerization reactions, by application or adaptation of the methods described in Adv. Carbohydr. Chem., 13, 63, (1958), in particular in basic medium by means of a dilute aqueous sodium hydroxide solution (0.03 to 0.05%), at a temperature of between 20 and 40 C.,
by chain-extension reactions, by application or adaptation of the methods described in xe2x80x9cThe Carbohydratesxe2x80x9d, edited by W. Pigman and D. Horton, Academic Press, New York, Volume IA, 133 (1972) and in particular by forming the cyanohydrin of the starting aldose (for example, by reaction with sodium cyanide in aqueous solution, at a temperature of between 10 and 30 C. and in the presence of sodium hydroxide, at a pH in the region of 9), then hydrolysis of the nitrile functional group thus formed to the corresponding acid by application or adaptation of the methods described in Organic Synthesis, Volume I, page 436 and Volume III, page 85 (for example, using concentrated sulphuric acid or hydrochloric acid, in aqueous solution, at a temperature of between 20 C. and the reflux temperature of the reaction mixture), and then reduction of the carboxylic acid functional group to the corresponding aldehyde by application or adaptation of the methods described in J. Am. Chem. Soc., 71, 122 (1949), in particular using an alkali metal borohydride (for example, sodium borohydride), in aqueous solution, at a temperature of between 20 C. and the boiling temperature of the reaction mixture,
by chain-shortening reactions, by application or adaptation of the methods described in xe2x80x9cThe Carbohydratesxe2x80x9d, edited by W. Pigman and D. Horton, Academic Press, New York, Volume IB, 1980, page 929 or Chem. Ber., 83, 559 (1950) and in particular by converting the aldehyde functional group of the aldose to the corresponding hydroxylamine by application or adaptation of the methods described in Organic Synthesis, Volume II, page 314 (for example, using hydroxylamine hydrochloride, in aqueous solution and in the presence of a base, such as sodium carbonate, at a temperature of between 20 and 50 C.), and then reaction with 3,4-dinitrofluorobenzene in the presence of carbon dioxide and a base, such as sodium hydrogencarbonate, in aqueous solution, and an aliphatic alcohol (for example, isopropyl alcohol), at a temperature of between 50 and 80 C.,
b) corresponding allyl alcohols, by application or adaptation of the methods described in Science, 220, 949 (1983) and in particular using tert-butyl hydroperoxide in the presence of a titanium (IV) complex, such as the titanium (IV) isopropoxide and optically pure dialkyl tartrate (for example, diethyl tartrate) complex, followed by successive reaction with sodium thiophenolate, para-chloroperbenzoic acid in acetic anhydride, and diisopropylaluminium hydride.
The derivatives of formula (II) can also be obtained by application or adaptation of the methods described in J. Am. Chem. Soc., 113 (21), 8137 (1991), Chem. Pharm. Bull., 35(7), 2894 (1987), Carbohydr. Res., 154, 127 (1986), Sen""i Gakkaihi, 35 (12), 525 (1979), Chem. Ber., 101 (7), 2294 (1968), J. Carbohydr. Chem., 3 (2), 219 (1984) and Tetrahedron, 40 (12), 2233 (1984) and Patents WO 9310137 and WO 89-US51089029.
The various stereoisomers of the compounds of formula (I) are obtained from the corresponding stereoisomers of the intermediates (II). Use is preferably made, among these stereoisomers, of 3-methoxy-D-glucopyranose, 3-fluoro-3-deoxy-D-glucose, 4-fluoro-4-deoxy-D-glucose, 6-amino-6-deoxy-D-glucose, D-glucuronic acid, D-galacturonic acid, D-glucuronamide and 3-deoxy-D-glucose.
It is understood by a person skilled in the art that, for the implementation of the processes according to the invention described above, it may be necessary to introduce protective groups for the amino, hydroxyl and carboxyl functional groups, in order to avoid side reactions. These groups are those which can be easily removed without affecting the remainder of the molecule. Mention may be made, as examples of protective groups for the amino functional group, of tert-butyl or methyl carbamates which can be regenerated by means of iodotrimethylsilane. Mention may be made, as examples of protective groups for the hydroxyl functional group, of trialkylsilyl (for example, triethylsilyl) or benzyl. Mention may be made, as protective groups for the carboxyl functional groups, of esters (for example, methoxymethyl ester, tetrahydropyranyl ester or benzyl ester), oxazoles and 2-alkyl-1,3-oxazolines. Other protective groups which can be used in these processes are also described by W. Greene et al., Protective Groups in Organic Synthesis, second edition, 1991, John Wiley and Sons and P. J. Kocienski, Protecting Groups, published by Thieme Verlag (1994).
The reaction mixtures obtained by the various processes described above are treated according to conventional physical (evaporation, extraction, distillation, chromatography or crystallization, for example) or chemical (formation of salts, for example) methods.
The compounds of formula (I) can optionally be converted to addition salts with an inorganic or organic acid by the action of such an acid in an organic solvent, such as an alcohol, a ketone, an ether or a chlorinated solvent.
These salts also form part of the invention.
Mention may be made, as examples of pharmaceutically acceptable salts, of the addition salts with inorganic or organic acids, such as acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulphonate, isethionate, theophyllinacetate, salicylate, methylenebis(xcex2-oxynaphthoate), hydrochloride, sulphate, nitrate and phosphate.
The preferred compounds of formula (I) are those mentioned above as active principle of the preferred medicaments, with the exception of the known products.
The following examples illustrate the invention: